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      Mice deleted for cell division cycle 73 gene develop parathyroid and uterine tumours: model for the hyperparathyroidism-jaw tumour syndrome

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          Abstract

          The hyperparathyroidism-jaw tumour (HPT-JT) syndrome is an autosomal dominant disorder characterized by occurrence of parathyroid tumours, often atypical adenomas and carcinomas, ossifying jaw fibromas, renal tumours and uterine benign and malignant neoplasms. HPT-JT is caused by mutations of the cell division cycle 73 ( CDC73) gene, located on chromosome 1q31.2 and encodes a 531 amino acid protein, parafibromin. To facilitate in vivo studies of Cdc73 in tumourigenesis we generated conventional ( Cdc73 +/−) and conditional parathyroid-specific ( Cdc73 +/L/ PTH-Cre and Cdc73 L/L / PTH-Cre) mouse models. Mice were aged to 18-21 months and studied for survival, tumour development and proliferation, and serum biochemistry, and compared to age-matched wild-type ( Cdc73 +/+ and Cdc73 +/+ /PTH-Cre) littermates. Survival of Cdc73 +/− mice, when compared to Cdc73 +/+ mice was reduced ( Cdc73 +/−=80% Cdc73 +/+=90% at 18 months of age, P<0.05). Cdc73 +/− , Cdc73 +/L /PTH-Cre and Cdc73 L/L /PTH-Cre mice developed parathyroid tumours, which had nuclear pleomorphism, fibrous septation and increased galectin-3 expression, consistent with atypical parathyroid adenomas, from 9 months of age. Parathyroid tumours in Cdc73 +/− , Cdc73 +/L /PTH-Cre and Cdc73 L/L /PTH-Cre mice had significantly increased proliferation, with rates >fourfold higher than that in parathyroid glands of wild-type littermates ( P<0.0001). Cdc73 +/− , Cdc73 +/L /PTH-Cre and Cdc73 L/L /PTH-Cre mice had higher mean serum calcium concentrations than wild-type littermates, and Cdc73 +/− mice also had increased mean serum parathyroid hormone (PTH) concentrations. Parathyroid tumour development, and elevations in serum calcium and PTH, were similar in males and females. Cdc73 +/− mice did not develop bone or renal tumours but female Cdc73 +/− mice, at 18 months of age, had uterine neoplasms comprising squamous metaplasia, adenofibroma and adenomyoma. Uterine neoplasms, myometria and jaw bones of Cdc73 +/− mice had increased proliferation rates that were 2-fold higher than in Cdc73 +/+ mice ( P<0.05). Thus, our studies, which have established mouse models for parathyroid tumours and uterine neoplasms that develop in the HPT-JT syndrome, provide in vivo models for future studies of these tumours.

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          Mutation and cancer: statistical study of retinoblastoma.

          A Knudson (1971)
          Based upon observations on 48 cases of retinoblastoma and published reports, the hypothesis is developed that retinoblastoma is a cancer caused by two mutational events. In the dominantly inherited form, one mutation is inherited via the germinal cells and the second occurs in somatic cells. In the nonhereditary form, both mutations occur in somatic cells. The second mutation produces an average of three retinoblastomas per individual inheriting the first mutation. Using Poisson statistics, one can calculate that this number (three) can explain the occasional gene carrier who gets no tumor, those who develop only unilateral tumors, and those who develop bilateral tumors, as well as explaining instances of multiple tumors in one eye. This value for the mean number of tumors occurring in genetic carriers may be used to estimate the mutation rate for each mutation. The germinal and somatic rates for the first, and the somatic rate for the second, mutation, are approximately equal. The germinal mutation may arise in some instances from a delayed mutation.
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            Galectins as modulators of tumour progression.

            Galectins are a family of animal lectins with diverse biological activities. They function both extracellularly, by interacting with cell-surface and extracellular matrix glycoproteins and glycolipids, and intracellularly, by interacting with cytoplasmic and nuclear proteins to modulate signalling pathways. Current research indicates that galectins have important roles in cancer; they contribute to neoplastic transformation, tumour cell survival, angiogenesis and tumour metastasis. They can modulate the immune and inflammatory responses and might have a key role helping tumours to escape immune surveillance. How do the different members of the Galectin family contribute to these diverse aspects of tumour biology?
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              Galectins: structure, function and therapeutic potential.

              Galectins are a family of animal lectins that bind beta-galactosides. Outside the cell, galectins bind to cell-surface and extracellular matrix glycans and thereby affect a variety of cellular processes. However, galectins are also detectable in the cytosol and nucleus, and may influence cellular functions such as intracellular signalling pathways through protein-protein interactions with other cytoplasmic and nuclear proteins. Current research indicates that galectins play important roles in diverse physiological and pathological processes, including immune and inflammatory responses, tumour development and progression, neural degeneration, atherosclerosis, diabetes, and wound repair. Some of these have been discovered or confirmed by using genetically engineered mice deficient in a particular galectin. Thus, galectins may be a therapeutic target or employed as therapeutic agents for inflammatory diseases, cancers and several other diseases.
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                Author and article information

                Journal
                Oncogene
                Oncogene
                Oncogene
                Nature Publishing Group
                0950-9232
                1476-5594
                13 July 2017
                13 March 2017
                : 36
                : 28
                : 4025-4036
                Affiliations
                [1 ]Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Radcliffe Department of Medicine, University of Oxford, Churchill Hospital , Oxford, UK
                [2 ]Department of Pathology, John Radcliffe Hospital, Headley Way , Oxford, UK
                [3 ]Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, MI, USA
                [4 ]Center for Cancer and Cell Biology, Van Andel Research Institute , Grand Rapids, MI, USA
                Author notes
                [* ]Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Radcliffe Department of Medicine, University of Oxford, Churchill Hospital , Oxford OX3 7LJ, UK Email: rajesh.thakker@ 123456ndm.ox.ac.uk
                Article
                onc201743
                10.1038/onc.2017.43
                5472200
                28288139
                b9729ea1-8cc8-4477-adfc-230f92e94bc6
                Copyright © 2017 The Author(s)

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 18 August 2016
                : 22 December 2016
                : 24 January 2017
                Categories
                Original Article

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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